This proposal is designed to use two recent observations made in our laboratory to determine the mechanisms by which antibodies to acetylcholine receptor (AChR) induce myasthenia gravis (MG). The observations, which run somewhat counter to current theories, are: l) monoclonal antibodies (mcabs) that block the function of intact AChR induce severe acute myasthenia in the absence of histological abnormalities; 2) chronic administration in rats of anti-AChR mcabs incapable of blocking AChR function results in the histological abnormalities of MG in the absence of clinical or electromyographic abnormality. We propose to determine the precise nature of the chronic syndrome to establish whether the histological abnormality has pathogenic significance or whether it represents the healed stage of a more severe endplate injury similar to the acute phase of experimental myasthenia (EAMG). We also propose to determine whether the addition of either mcabs that block AChR function, mcabs more efficient in inducing increased AChR turnover, or combinations of many mcabs are required to produce the complete MG picture of histological, clinical, and electrophysiological abnormalities. We will make use of purified anti-AChR mcabs and Ig fragments and will study clinical weakness, electromyographic function, miniature endplate potential amplitudes, muscle content of AChR and AChR-mcab complexes, light and electron microscopic changes, and a number of serological and immune parameters. The combination of immunological, biochemical, electrophysiological, and pathological techniques should provide information on the sequence of events that leads to MG. This information may well suggest new means of treating or preventing this disease. In addition, since our present knowledge of MG makes it a "model" autoimmune disease, the information gained in this study will likely be applicable to other less well-understood autoimmune diseases.